Lpr and gld are single, recessive, autosomal genes which are non- complementary and which each induce similar syndromes of systemic autoimmunity and lymphoproliferation. The lpr gene has recently been determined to code for a defective form of the Fas apoptosis receptor, while the gld codes for a defective form of the Fas ligand. By using mixed cellular chimeras of congenic mouse strains, we have previously demonstrated that both the B cells and T cells in lpr mice express intrinsic abnormalities that are essential to the autoimmune syndrome. In parallel experiments with gld mice, we have found that in gld/+ mixed chimeras, the gld B cells do not show the striking preferential production of immunoglobulins and autoantibodies found in lpr/+ double chimeras, nor does lymphadenopathy occur. This indicates that the gld defect is extrinsic to the B cells that produce autoantibodies and the T cells that hyperaccumulate in this model. Further data have suggested that the Fas ligand may function in an autocrine manner as well. In the present application, we will determine the cellular source of the normal presumed Fas ligand that is supplied by the co-transferred +/+ bone marrow and determine the specificity of Fas/Fas ligand interaction. The Specific Aims of the current proposal are: l) Does the expression of Fas ligand by B cells suppress gld disease? Although our preliminary data suggest that the answer to this question is "no," we have reservations regarding this conclusion. The proposed experiments will clarify this important issue. 2) What specific cell types produce the Fas ligand? The phenotype of the cells will clarify this important issue. 3) What is the specificity of the cells involved in Fas/Fas ligand interactions? If direct cell-cell communication is required (rather than the release of a soluble factor), we should be able to define the antigenic or receptor specificity of the Fas ligand bearing cell. 4)What cell populations express Fas ligand protein? An antibody to Fas ligand will be produced and use to detect cell-surface expression. These studies will thus help elucidate the in vivo functional effects of Fas/Fas ligand interactions in immunoregulation and tolerance induction. This understanding of the mechanism of action of the lpr and gld genetic defects will focus future research aimed at elucidating the causal mechanisms of human SLE.